A refined and translationally relevant model of chronic DSS colitis in BALB/c mice

2017 ◽  
Vol 52 (3) ◽  
pp. 240-252 ◽  
Author(s):  
Maximilian Hoffmann ◽  
Ulla Schwertassek ◽  
Aleksandra Seydel ◽  
Klaus Weber ◽  
Werner Falk ◽  
...  
Keyword(s):  
Dextran Sulfate ◽  
Significant Loss ◽  
Refined Model ◽  
Relevant Model ◽  
Dss Colitis ◽  
Clinical Scores ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Colitis Model ◽  
Pro Inflammatory Cytokines

Inflammatory bowel diseases (IBD) are chronic relapsing disorders of the gastrointestinal tract. Several mouse models for IBD are available, but the acute dextran sulfate sodium (DSS)-induced colitis model is mostly used for preclinical studies. However, this model lacks chronicity and often leads to significant loss of mice. The aim of this study was to establish a refined and translationally relevant model of DSS chronic colitis in BALB/c mice. In the first part, we compared several standard therapeutic (ST) treatments for IBD in the acute DSS colitis model to identify the optimal treatment control for a DSS colitis model as compared to literature data. In the second part, we tested the two most effective ST treatments in a refined model of chronic DSS colitis. Cyclosporine A (CsA) and 6-thioguanine (6-TG) caused considerable reduction of clinical scores in acute DSS colitis. The clinical outcome was confirmed by the results for colon length and by histopathological evaluation. Moreover, CsA and 6-TG considerably reduced mRNA expression of several pro-inflammatory cytokines in spleen and colon. Both compounds also showed a substantial therapeutic effect in the refined model of chronic DSS colitis with regard to clinical scores and histopathology as well as the expression of inflammatory markers. The refined model of chronic DSS colitis reflects important features of IBD and is well suited to test potential IBD therapeutics.

Vitamin D/VDR signaling inhibits colitis by suppressing HIF-1α activation in colonic epithelial cells

2021 ◽  
Author(s):  
Gang Xue ◽  
Ruifang Gao ◽  
Zhuanzhuan Liu ◽  
Na Xu ◽  
Yong Cao ◽  
...  
Keyword(s):  
Vitamin D ◽  
Animal Models ◽  
Epithelial Cells ◽  
Dextran Sulfate ◽  
Hypoxia Inducible Factor ◽  
Dependent Manner ◽  
Trinitrobenzenesulfonic Acid ◽  
Colonic Epithelial Cells ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Vitamin D/vitamin D receptor (VDR) signaling is reported to have a protective effect on the onset or progression of inflammatory bowel diseases (IBD) and hypoxia-inducible factor 1α (HIF-1α) activation is demonstrated to be closely associated with chemical-induced colitis. However, the association between vitamin D/VDR signaling and HIF-1α on IBD development remains a mystery. Here, we showed that HIF-1α expression was largely increased in the colonic epithelial cells of diseased tissues from ulcerative colitis (UC) patients. Consistently, HIF-1α activation was also improved in colonic epithelial cells upon TNFα treatment in a NF-κB pathway-dependent manner. HIF-1α inhibitors treatments ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis in animal models. In cell or colitis animal models, vitamin D/VDR signaling suppressed HIF-1α overexpression in colonic epithelial cells via regulating NF-κB pathway, resulting in the inhibition of IFNγ and IL-1β overproductions in these cells. Collectively, these data suggest that vitamin D/VDR signaling relieves colitis development in animal models, at least in part, by suppressing HIF-1α expression in colonic epithelial cells.

scholarly journals Pharmacological Evaluation of the SCID T Cell Transfer Model of Colitis: As a Model of Crohn's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Thomas Lindebo Holm ◽  
Steen Seier Poulsen ◽  
Helle Markholst ◽  
Stine Reedtz-Runge
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Adoptive Transfer ◽  
Inflammatory Bowel Diseases ◽  
Transfer Model ◽  
Drug Candidates ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
T Cell Transfer ◽  
Colitis Model

Animal models are important tools in the development of new drug candidates against the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. In order to increase the translational value of these models, it is important to increase knowledge relating to standard drugs. Using the SCID adoptive transfer colitis model, we have evaluated the effect of currently used IBD drugs and IBD drug candidates, that is, anti-TNF-α, TNFR-Fc, anti-IL-12p40, anti-IL-6, CTLA4-Ig, anti-α4β7 integrin, enrofloxacin/metronidazole, and cyclosporine. We found that anti-TNF-α, antibiotics, anti-IL-12p40, anti-α4β7 integrin, CTLA4-Ig, and anti-IL-6 effectively prevented onset of colitis, whereas TNFR-Fc and cyclosporine did not. In intervention studies, antibiotics, anti-IL-12p40, and CTLA4-Ig induced remission, whereas the other compounds did not. The data suggest that the adoptive transfer model and the inflammatory bowel diseases have some main inflammatory pathways in common. The finding that some well-established IBD therapeutics do not have any effect in the model highlights important differences between the experimental model and the human disease.

scholarly journals Animal models for inducing inflammatory bowel diseases: integrative review

2021 ◽  
Vol 11 (1) ◽  
pp. 80-87
Author(s):  
Nadja Maria da Costa Melo ◽  
Marília Virgo Silva Almeida ◽  
Daniel Melo de Oliveira Campos ◽  
Claudio Bruno Silva de Oliveira ◽  
Jonas Ivan Nobre Oliveira
Keyword(s):  
Acetic Acid ◽  
Animal Models ◽  
Inflammatory Bowel Diseases ◽  
Intestinal Inflammation ◽  
Integrative Review ◽  
Chemical Models ◽  
Experimental Induction ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Colitis Model

Objective: To identify and describe comparatively the chemical models of the induction of inflammatory bowel diseases (IBD) in rodents most used and that best mimic the pathogenesis in humans. Methods: Based on an integrative review in the MEDLINE and LILACS databases, it was investigated which experimental induction models were most cited in articles published from 2004 to 2020, with the descriptors "Colitis/CI", "Colitis model ulcerative" and "Intestinal inflammation model." All empirical articles that addressed one or more inflammation models in rats or mice were included. Results: 239 articles were identified; of these, only ten empirical articles were selected. The most used models were colitis induced by TNBS acid, DSS, and colitis induced by acetic acid (AA). Conclusion: It was possible to identify the most used models to promote the induction of intestinal inflammation in rats, and both models proved to be effective according to the limitations observed in the models described, suggesting the need for new works that use more well-defined protocols and that more fully represent the pathophysiological complexity of the disease.

scholarly journals The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis

2018 ◽  
Author(s):  
Annika Wyss ◽  
Tina Raselli ◽  
Gérard Schmelczer ◽  
Glynis Klinke ◽  
Nathan Perkins ◽  
...  
Keyword(s):  
Immune System ◽  
Gene Encoding ◽  
Barr Virus ◽  
Dss Colitis ◽  
Inflammatory Bowel ◽  
Epstein Barr ◽  
Lymphoid Structures ◽  
G Protein Coupled ◽  
Colitis Model

AbstractThe gene encoding for Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7α,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied.We found increased mRNA expression of EBI2 and oxysterol synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated extraintestinal levels of 25-hydroxylated oxysterols, including 7α,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2-/- mice in the IL-10 colitis model.The colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2-/- mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures.In summary, we report induction of the EBI2-7α,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7α,25-dihydroxycholesterol axis in IBD pathogenesis.

scholarly journals Mesenchymal stem cells and acellular products attenuate murine induced colitis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Li ◽  
Jessica Altemus ◽  
Amy L. Lightner
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Comparative Investigation ◽  
Inflammatory Disorder ◽  
Tissue Repair And Regeneration ◽  
Dss Colitis ◽  
Stat3 Signaling ◽  
Cytokine Analysis ◽  
Inflammatory Bowel ◽  
Colitis Model

Abstract Background Mesenchymal stem cells (MSCs) are a well-established immunomodulatory agent which can also promote tissue repair and regeneration. Recent studies have demonstrated MSCs as a novel therapeutic for inflammatory bowel disease (IBD), a chronic idiopathic inflammatory disorder of the gastrointestinal tract. However, the precise role of MSCs in regulating immune responses is controversial, and its significance in the pathogenesis remains IBD undefined. In addition, MSCs’ acellular product, extracellular vesicles (EVs), may also play an important role in the armamentarium of therapeutics, but how EVs compare to MSCs remains unknown due to the lack of side-by-side comparative investigation. We herein compared MSCs and MSC-derived EVs for the treatment of IBD using a DSS-induced colitis model. Methods A DSS-induced colitis model was used. At day 4, mice received adipose-derived MSCs, MSC-derived EVs, or placebo. Weight loss, stool consistency, and hematochezia was charted. At day 8, murine colons were harvested, histologic analysis performed, and serum/tissue cytokine analysis conducted. Results MSCs and EVs demonstrated equivalent immunosuppressive function in DSS-treated mice through decreased colonic lymphocyte infiltration and attenuated disease severity after both MSC and EV treatment. Furthermore, both MSCs and EVs have an equivalent ability to inhibit inflammation in the DSS colitis model by inhibiting JAK, JNK 1/2, and STAT3 signaling. Conclusions These results suggest that (i) both MSCs and EVs are effective therapeutic candidates for a DSS-induced mouse colitis model, (ii) MSCs and EVs have similar immunosuppressive and anti-inflammatory functions, and (iii) EVs may present a novel future therapeutic for the treatment of IBD.

Curcumin Inhibits T Follicular Helper Cell Differentiation in Mice with Dextran Sulfate Sodium (DSS)-Induced Colitis

2021 ◽  
pp. 1-19
Author(s):  
Hai-Yan Wang ◽  
Wei Ge ◽  
Su-Qing Liu ◽  
Jian Long ◽  
Qing-Qing Jiang ◽  
...  
Keyword(s):  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Curcuma Longa ◽  
Colon Tissue ◽  
Change Rate ◽  
Protein Levels ◽  
Follicular Helper ◽  
Inflammatory Bowel ◽  
T Follicular Helper Cell ◽  
Pro Inflammatory Cytokines

Follicular helper T cells (Tfh) regulate the differentiation of germinal center B cells and maintain humoral immunity. Notably, imbalances in Tfh differentiation often lead to the development of autoimmune diseases, including inflammatory bowel disease (IBD). Curcumin, a natural product derived from Curcuma longa, is effective in relieving IBD in humans and animals, and its mechanisms of immune regulation need further elaboration. In this study, dextran sodium sulfate induced ulcerative colitis in BALB/c mice, and curcumin was administered simultaneously for 7 days. Curcumin effectively upregulated the change rate of mouse weight, colonic length, down-regulated colonic weight, index of colonic weight, colonic damage score and the levels of pro-inflammatory cytokines IL-6, IL-12, IL-23 and TGF-[Formula: see text]1 in colonic tissues of colitis mice. Importantly, curcumin regulated the differentiation balance of Tfh and their subpopulation in colitis mice; the percentages of Tfh (CD4[Formula: see text]CXCR5[Formula: see text]BCL-6[Formula: see text], CD4[Formula: see text]CXCR5[Formula: see text]PD-1[Formula: see text], CD4[Formula: see text]CXCR5[Formula: see text]PD-L1[Formula: see text], CD4[Formula: see text]CXCR5[Formula: see text]ICOS[Formula: see text], Tfh17 and Tem-Tfh were downregulated significantly, while CD4[Formula: see text]CXCR5[Formula: see text]Blimp-1[Formula: see text], Tfh1, Tfh10, Tfh21, Tfr, Tcm-Tfh and Tem-GC Tfh were upregulated. In addition, curcumin inhibited the expression of Tfh-related transcription factors BCL-6, p-STAT3, Foxp1, Roquin-1, Roquin-2 and SAP, and significantly upregulated the protein levels of Blimp-1 and STAT3 in colon tissue. In conclusion, curcumin may be effective in alleviating dextran sulfate sodium-induced colitis by regulating Tfh differentiation.

scholarly journals Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Sean P. Kessler ◽  
Dana R. Obery ◽  
Carol de la Motte
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Experimental Colitis ◽  
Hyaluronan Synthase ◽  
Wild Type ◽  
Colon Tissue ◽  
Dss Colitis ◽  
Chemically Induced ◽  
Inflammatory Bowel ◽  
Colitis Model

Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice null for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 null mice are protected from colitis, compared to wild-type and HAS1 null mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 null mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium

2006 ◽  
Vol 291 (2) ◽  
pp. G364-G371 ◽  
Author(s):  
Edward S. Kimball ◽  
Craig R. Schneider ◽  
Nathaniel H. Wallace ◽  
Pamela J. Hornby
Keyword(s):  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Cannabinoid Receptor ◽  
Experimental Colitis ◽  
Receptor Activation ◽  
Enteric Neurons ◽  
Cannabinoid Receptor 1 ◽  
Dss Colitis ◽  
Selective Agonist ◽  
Colitis Model

Oil of mustard (OM) is a potent neuronal activator that is known to elicit visceral hyperalgesia when given intracolonically, but the full extent to which OM is also proinflammatory in the gastrointestinal tract is not known. We have previously shown that male CD-1 mice given a single administration of 0.5% OM develop a severe colitis that is maximum at day 3 and that gradually lessens until essentially absent by day 14. OM-induced neuronal stimulation is reported to be reduced by cannabinoid agonists, and cannabinoid receptor 1 (CB1R)−/− mice have exacerbated experimental colitis. Therefore, we examined the role of cannabinoids in this OM-induced 3-day model of colitis in CD-1 mice and in a 7-day dextran sulfate sodium (DSS) colitis model in BALB/c mice. In OM colitis, the CB1R-selective agonist ACEA and the CB2R-selective agonist JWH-133 reduced ( P < 0.05) colon weight gain (means ± SE; 82 ± 13% and 47 ± 15% inhibition, respectively), colon shrinkage (98 ± 24% and 42 ± 12%, respectively), colon inflammatory damage score (49 ± 11% and 40 ± 12%, respectively), and diarrhea (58 ± 12% and 43 ± 11%, respectively). Histological damage was similarly reduced by these treatments. Likewise, CBR agonists attenuated DSS colitis, albeit at higher doses; ACEA at 10 mg/kg, twice daily, inhibited ( P < 0.05) macroscopic and microscopic scores (46 ± 9% and 63 ± 7%, respectively); whereas 20 mg/kg, twice daily, of JWH-133 was required to diminish ( P < 0.05) macroscopic and microscopic scores (29 ± 7% and 43 ± 5%, respectively). CB1R and CB2R immunostaining of colon sections revealed that CB1R in enteric neurons was more intense in colitic vs. control mice; however, CB1R was also increased in the endothelial layer in OM colitis only. CB2R immunostaining was more marked in infiltrated immune cells in OM colitis. These findings validate the OM colitis model with respect to the DSS model and provide strong support to the emerging idea that cannabinoid receptor activation mediates protective mechanisms in experimental colitis. The demonstration of CB1R agonist effects in colitis support the neurogenic nature of the OM-induced colitis model and reinforce the importance of neuronal activation in intestinal inflammation.

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